Interleukin 7 (IL-7) is vital for the development of the immune system and profoundly enhances the functions of mature T cells. Chronic administration of IL-7 to mice markedly increases T-cell numbers especially CD8+ T cells, and enhances T-cell functional potential. However, the mechanism by which these effects occur remains unclear. The results that our laboratory have generated this year demonstrated that only 2 days of IL-7 treatment is needed for maximal enhancement of T-cell function, as measured by proliferation, with a 6- to 12-fold increase in the proportion of CD4+ and CD8+ T cells that enter cell cycle within the first 24 hours of ex vivo stimulation. Biochemical analyses of G1 proteins important for the initiation of cell cycle demonstrated for the first time that 2-day IL-7 administration increases the levels of cdk2 kinase activity, cyclin E and phosphorylated Rb in leukocytes. Furthermore, cell cycle analysis revealed that administration of IL-7 in vivo increases basal proliferation by 4-fold and 14-fold in CD4+ and CD8+ T cells, respectively. These effects occurred in the absence of increases in cytokine production and most activation markers. Thus, IL-7 induced a homeostatic increase in the basal proliferation of T cells, especially CD8+ T cells. Moreover, we have demonstrated that this enhanced basal proliferation is the basis for the increase in T-cell numbers that occurs with IL-7 treatment in vivo. Specifically, IL-7 induced an additional 60% and 85% of resting CD4+ and CD8+ splenic T cells, respectively, to enter cell cycle in mice treated with IL-7 for 7 days. These results demonstrated for the first time that in vivo administration of IL-7 increases T-cell numbers and functional potential via a homeostatic, non-activating process. These findings suggest a unique clinical niche for IL-7 as a vaccine adjuvant or to ameliorate immunosuppression in that IL-7 therapy may increase T-cell numbers and enhance responses to specific antigenic targets while avoiding a general non-specific activation of the T-cell population.